1. Kinesyx™ Oligomer Technology for Drug Delivery:
Cardiovascular Combination Products
Bradley Strauss MD, PhD, FACC

2. Bradley H. Strauss, MD, PhD
DISCLOSURES
Bradley H. Strauss, MD, PhD
Royalty
Baylis Medical
Consulting Fees
Abbott Vascular, Interface Biologics
Ownership Interest (Stocks, Stock Options or Other Ownership Interest)
Matrizyme Pharma

3. Kinesyx™ Oligomer Drug Delivery Platform Synthesis and Properties
Diol
Diisocyanate
F group
Carbamate OH
Diol HO
Diisocyanate
NCO
OCN
F group HO
PU Linear Oligomeric Molecules
Condensation Reaction
Backbone Contains Carbamate
(-NHCO2) Functional Groups
Fluorinated Segments
Drug or Peptide
PU = Polyurethane

4. Kinesyx™ Technology: Benefits for Cardiovascular and Combination Products
Molecular structure
Benefits of fluorine application (drug shielding, reduced thrombus)
Robust library of formulations for rational drug delivery design
Tailored pharmaceutical release profile
Tailored material residency profile
Bio-elimination properties
Transient and sustained release pharmaceutical delivery platform

5. Formulation Library – SR and TR Drug Delivery
Robust Parameters for Rational Design
We have developed a versatile library of molecules with suitable parameters covering a range of properties for drug delivery. 5

6. Kinesyx™ Technology:
Tailored Pharmaceutical Release and Polymer Residency Profile
Release Profile:
- MTD
- Therapeutic Index
Oligomer Design:
- Chemical and Physical
Properties
- Biocompatibility 6

7. Formulation Biocompatibility Score
Inflammatory
- U937
- TNF
- Complement
Endothelial Migration Rate
- Boydon Chamber
- Wound Healing Assay
Cytotoxicity - ISO10993
Fresh scratch
Control
Control
KS 30
Paclitaxel
KS 48

8. Kinesyx™ Technology as Stent Coating Pharmaceuticals Delivery Platform
Additive
- Improves properties of durable polymers
- Reduce thrombogenecity up to 40% in an ex-vivo model
Stand Alone Low Molecular Weight Drug Delivery Coating with Bio-elimination Properties
- Low molecular weight oligomeric structure
- Adaptable in chemical composition
- Adaptable for mass loss and pharmaceutical release profile
- Adaptable for pharmaceutical loading capacity
stent strut

9. Kinesyx™ Technology
Reduced Thrombogenecity, Vascular Compatibility and Drug Release
Reduced Thrombogenecity
Cone and Plate
Bovine Blood Loop
Primate AV Shunt
Vascular Compatibility
Porcine Model
Thirty (30) Days
Histomorphometric Analysis
PTx Release Profile
8.8% Drug Loading
Pre and Post Sterilization
ETO
BMS
BPS7
+KA
Tested the blood compatibility……… 9

10. Vascular Compatibility - 30 Days
BMS
BPS 7
BPS 7 + KF
BPS 7 = Durable polymer A
SJTRI - Dr. N. Chronos and Professor Keith Robinson

11. The A-V Shunt Model - Primate Model
Hematologic
Parameters
Baboon Man
Hematocrit
Platelet count
320, ,000
WBC count
,000
Fibrinogen
Hematologic Parameters – Similarities between baboon and human blood clotting
Jamea Hampton, Department of Medicine and Neurocardiology Research Centre, University of Oklahoma Medical Centre 11

12. Assessment of Stent Thrombosis
Control Control+KA
BPS BPS7+KA

13. 40% Reduction of Platelet Deposition In a Primate Model
BMS, BPS 7 and BPS 7 + KF
BPS 7 vs. BPS 7 + KF: 40% REDUCTION AT 60 MINUTES (n=12)
BMS
BPS 7
We used a base polymer currently used in a commercially available product.
Stents were coated, crimped and sterilized.
Blood – No antiplatelet or anticoagulant was used.
Pt was labeled with indium III.
X-axis (time)
Y-axis (Pt deposition)
BPS 7
+ KF
BPS 7 = Durable Polymer A
BMS = Bare Metal Stent
Professor. S. Hanson, OHSU 13

14. Kinesyx™ Technology Transient DD for Stent Coatings
The Kinesyx™ oligomers can be designed to leave the surface at a controlled rate.
These self eliminating formulations can be loaded with therapeutics.
Short residency time of the coating.
Example of the device being stamped with DDS and return to its original form within a defined timeline 14

15. Incorporating Drugs into Coating
30 wt% Paclitaxel wt% Rapamycin
In addition we looked at loading parameters of the oligomer too. 15

16. PTx Release Profile Interms of drug release:
This slide shows the ability to formulate drugs with different release profile – controlling the rate of DES to BMS..
8.8% PTX:BPS7 16

17. PTx Release Profile

18. Platelet Adhesion and Fibrinogen Adsorption
Platelets
Fibrinogen
Kinesyx™ Self Eliminating
Formulations
For this experiment human blood was used and the platelets were labeled with 51Cr and Fib was labeled with 125I.
The cones were rotated at 200 rpm (300 s-1) for 15 minutes. The shear rate = 300 s-1. Heparin = 0.2U/ml.
PE is a general control
SS is control 1 for IBI test
Plot – Significant reduction
SS KS KS1: KS KS15 18

19. U937 Adhesion Profile
The adhesion of invitro differentiated macrophage-like U937 cells was reduced on doped surfaces compare to the controlled sample.
Monocyte-like human histocytic lymphoma cell line U937 can be induced with phorbol myristate acetate (PMA) to undergo differentiation into a macrophage-like phenotype.
Cell loading at per well
Min detection level 500
CyQuant lysine/dye
Fluorescent microplate reader – excitation 492, emission 540 19

20. Migration Of HCAEC: Determining the Effect of SE Coating
Boydon Chamber – Filters coated by the test formulation – SEM run to make sure the pores were not blocked.
And graph – X-axis shows formulation and Y-axis no of cells
SE SE + 1% PTX SE + 10%PTX BPS Control Control 20

21. Endothelial Cell Migration and Matrix Response
HCAEC on SS
Durable
HCAEC on EVA
PCAEC on SS
Increased EC migration and
repopulation on bare metal
surface

22. Coating Integrity Post Drug Release
Only Bare Metal Stent Remains after Drug Release
KF + PTx Bare Metal Stent
Before Incubation After 15 days incubation in buffer

23. Kinesyx™ Technology as Balloon Coating Drug Eluting Balloon
Fluorine chemistry:
- “protects” drug on
balloon surface
Reduced drug loss during transfer/access
Large dose delivery
Minimize unwanted release or dumping effect

24. Drug Retention Pharmaceutical Release: - Long Lesion:
Dose response - MTD
- Formulation:
Pharmaceutical release profile
Dip coating

25. In Vivo Porcine Coronary Studies
Formulation, pharmaceutical compatibility, dose and surface area correlation, and coating
Phase One: In Vivo
Tissue retention – Pharmaceutical Screening
Phase Two: In Vivo
Safety and Efficacy

26. Conclusions Novel Surface Modifying Oligomer Coatings
Reduce Surface Mediated Thrombus Formation
Vascular Compatible at 30 Days
Short Residency Time of the Coating with Bio-elimination Properties
Only Bare Metal Stent Remains Long Term
Titratable Pharmaceutical Release Profile for Hydrophobic and Hydrophilic drugs
Titratable Coating Residency Time
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